Scientists find genetic pathway to potent anticancer agents

Exploring the genomes of two different but related soil microbes, scientists from the University of Wisconsin-Madison have found the genes that govern the production of a class of highly potent anticancer agents.

Writing in two papers to be published this week in the journal Science, UW-Madison pharmaceutical sciences professors Jon Thorson and Ben Shen describe the discovery of genetic elements in soil-dwelling bacteria that are responsible for producing toxins that are among the most effective anticancer agents known.

The separate but complimentary findings portend the practical advent of a powerful new family of drugs to treat certain cancers.

'This molecule is so potent that it has to be directed to a particular target,' says Thorson. 'With this, all you need are one or two molecules and you can kill the (cancer) cell. These are different than most anticancer agents out there.'

The genetic pathways found by Shen and Thorson produce chemicals known as enediynes. Discovered in the 1960s, scientists have long been intrigued by the potential of these natural toxins produced by soil bacteria. But enediynes\' complicated chemical structure (first elucidated in 1985) and extreme reactivity have made them difficult to synthesize and use through conventional means.

The discovery of the genes that produce these agents means that enediynes can now be produced in quantity and their characteristics manipulated to make them far easier to use as therapeutic agents.

'We've found the genetic raw material to produce these compounds,' Shen says. 'With the genes in hand, we can take them apart and put them back together and that will allow improvements in production and development of new compounds' to treat cancer.

Working in two different species of soil bacteria, one from North America and one from China, Shen and Thorson found enediyne genetic pathways that are extremely similar, suggesting that the microbes that produce this class of toxins evolved in the distant past from a common ancestor. In nature, the microbes that make enediynes tend to be slow growing and produce the toxin to keep from being overwhelmed by more prolific competing microorganisms.

Enediynes work by cleaving or shearing the target cell's DNA. Because the enediynes are so effective, more than 1,000 times more potent than some of the most effective antitumor agents now in use, it takes very little to kill a cell.

'This molecule is so lethal it has to be directed to a particular target. It can be tethered to an antibody which then directs it to the cancer cell,' Thorson explains.

The ability to precisely home in on cancer cells with such small amounts of a drug may also help limit some of the unpleasant side effects of chemotherapy such as nausea and hair loss.

Members of the enediyne family are already in clinical use to treat various cancers such as acute myeloid leukemia. But their use has been severely limited by the complicated nature of the enediyne molecules. The complex structure requires as many as 50 steps to make the synthetic molecule, imposing a severe limiting factor on the availability of enediyne-based antitumor drugs.

With a map of the genetic pathway that governs the enediyne microbes' ability to produce the toxin, scientists can now use other methods to culture the microbe in quantity and extract the enediynes for use in research and the clinic.

'These are tamable microbes and this lays the groundwork for the amount of the molecule that you can produce through fermentation,' says Shen. 'Through genetic engineering, we can also now alter the enediynes' reactivity, and address issues of metabolism and production.'

The work underpinning both the Shen and Thorson papers was supported by the National Institutes of Health.